As the immune system ages, a complex set of alterations resulting in well documented immunosenescence and immunodeficiencies in elderly individuals. This diminished responsiveness to new pathogens and poor maintenance of memory lymphocyte populations are increasingly common with age, and contribute to the increased morbidity and mortality in the elderly population. Disrupted immune function includes both deficiencies in peripheral lymphocyte homeostasis and maturation. Our lab is interested in the gene expression networks that orchestrate the CD8+ T cell response to infection, and mediate the longevity of CD8+ T cell immunological memory. CD8+ T cells are indispensable in defending the host against intracellular pathogens. Within days of infection, a nave pathogen-specific T cell undergoes a massive proliferative burst while acquiring the ability to secrete effector cytokines and cytolytic molecules to eliminate the invading pathogen. At the same time, these proliferating cells further differentiate into short-lived effector T cells that will die upo clearance of the infection, and memory-precursor T cells that have the capacity to survive for decades to protect against re-infection with the same pathogen. E proteins are basic helix loop helix (bHLH) proteins, which are a diverse group of transcription factors that have been implicated in many cell processes such as activation, differentiation and lineage commitment in the immune system. Our lab previously showed that E proteins and their inhibitors Id proteins, together regulate differentiation of both the short-lived effector and memory-precursor populations in CD8+ T cells. One particular E protein, E2A, is known to be dysregulated in aged mice, resulting in a decreased immune response to infection. Basic helix-loop-helix family, member e40 (Bhlhe40), is a bHLH transcription factor that is related to the E proteins, and is highly expressed in CD8+ T cells. We are particularly interested in the function of Bhlhe40 because it may also mediate key immune processes and regulate similar transcriptional programs as the E and Id proteins. I hypothesize that Bhlhe40 is required for the function of CD8+ T cells by modulating E protein activity and is necessary for CD8+ T cells to respond to pathogens. It is the goal of this project to establish the role of Bhlhe40 in CD8+ T cell activatio, maintenance and memory formation, to understand the transcriptional programs involved, and assess how these change as the immune system ages. By characterizing the role that Bhlhe40 plays in CD8+ T cells, we hope to expand our understanding of how the immune system maintains a competent memory population in aged individuals and identify targets that may potentiate immune memory and protection with age.